Water → 5-(1-(2-Hydroxyethyl)-1H-pyrazol-4-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide

HRID 629106Notes

Reaction equation

HRID 629106 reaction equation
Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].O1CCCCC1[O:28][CH2:29][CH2:30][N:31]1[CH:35]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:33]=[N:32]1.C([O-])([O-])=O.[K+].[K+].O>O1CCOCC1>[OH:28][CH2:29][CH2:30][N:31]1[CH:35]=[C:34]([C:2]2[CH:3]=[N:4][CH:5]=[C:6]([CH:21]=2)[C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=2)=[O:8])[CH:33]=[N:32]1

Participants

6

Reactant 4

HCID 962WaterHCID 11430Potassium CarbonateHCID 46840185-bromo-N-(4-(trifluoromethoxy)phenyl)nicotinamideHCID 593418191-[2-(oxan-2-yloxy)ethyl]-4-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole

Product 1

HCID 722035705-(1-(2-Hydroxyethyl)-1H-pyrazol-4-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide

Reagents, catalysts & solvents 1

HCID 312751,4-DioxaneSolvent

Conditions

Temperature
95 °C

Procedure

5-Bromo-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 61.1, 181 mg, 0.5 mmol), 1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (193 mg, 0.600 mmol), PdCl2(dppf)-(CH2Cl2) (20.42 mg, 0.025 mmol), K2CO3 (138 mg, 1 mmol), water (2 mL) and dioxane (10 mL) were added to a vial, which was sealed, evacuated/purged with argon and the RM was stirred at 95° C. 7 h. The RM was treated with water and extracted with EtOAc. The combined extracts were dried over Na2SO4 and the solvent was evaporated off under reduced pressure to give a residue which was purified by flash chromatography (Silica gel column, 25 g, EtOAc). The purified intermediate was treated with 5 M HCl in MeOH (5 mL) and stirred at RT for 1 h. The solvent was evaporated off under reduced pressure and the residue was treated with aq. NaHCO3 and extracted with EtOAc. The combined extracts were washed with water and brine, dried over Na2SO4, and the solvent was evaporated off under reduced pressure to give the product which was recrystallized from Et2O/EtOAc afford the title compound as a beige powder. UPLC-MS (Condition 2) tR 0.92 min, m/z=393.2 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 3.78 (q, J=5.47 Hz, 2H) 4.19 (t, J=5.47 Hz, 2H) 4.96 (t, J=5.08 Hz, 1H) 7.40 (d, J=8.60 Hz, 2H) 7.90 (d, J=8.99 Hz, 2H) 8.09 (s, 1H) 8.38 (s, 1H) 8.43 (d, J=1.17 Hz, 1H) 8.88 (s, 1H) 9.03 (s, 1H) 10.63 (s, 1H).

Workup

  1. customwas sealed
  2. customevacuated/purged with argon
  3. custom7 h
  4. additionThe RM was treated with water
  5. extractionextracted with EtOAc
  6. dry with materialThe combined extracts were dried over Na2SO4
  7. customthe solvent was evaporated off under reduced pressure
  8. customto give a residue which
  9. customwas purified by flash chromatography (Silica gel column, 25 g, EtOAc)
  10. additionThe purified intermediate was treated with 5 M HCl in MeOH (5 mL)
  11. stirringstirred at RT for 1 h
  12. customThe solvent was evaporated off under reduced pressure
  13. additionthe residue was treated with aq. NaHCO3
  14. extractionextracted with EtOAc
  15. washThe combined extracts were washed with water and brine
  16. dry with materialdried over Na2SO4
  17. customthe solvent was evaporated off under reduced pressure
  18. customto give the product which
  19. customwas recrystallized from Et2O/EtOAc

Sources & evidence

ORD record
ord-4ee8080b93604ce69df5e78df2dbb630
Source dataset
uspto-grants-2016_04
Patent number
US09315489B2

Reaction notes

Loading…